Deficiency of inducible nitric oxide synthase alleviates dermal fibrosis and inflammation in scleroderma.

Abstract

Scleroderma is a connective tissue disorder marked by chronic inflammation and progressive skin fibrosis. Abnormal activation of fibroblasts (FBs) and deposition of collagen in the extracellular matrix (ECM) are the key to the progression of scleroderma. While FBs activation has been attributed to the dysfunction of keratinocytes (KCs) and immune cells, the crosstalk among these cells is considered critical for scleroderma progression. Recent evidence indicates that inducible nitric oxide synthase (iNOS) is highly expressed in scleroderma lesions, and iNOS contributes to the progression of dermatoses. Nevertheless, the specific role of iNOS in scleroderma remains to be fully elucidated. We utilized a bleomycin (BLM)-induced scleroderma model in wildtype (WT) and iNOS knockout (iNOS KO) mice to investigate the function of iNOS in scleroderma. We demonstrated that iNOS deficiency alleviated scleroderma progression, inhibiting inflammatory factor expression in KCs and neutrophils (Neus) infiltration. Subsequently, we stimulated FBs with TNF-α and IL-1β, which are mainly expressed by KCs and Neus, and confirmed that iNOS deletion attenuated FBs activation. We also revealed that iNOS inhibitors significantly attenuated the severity of scleroderma lesions. Our study collectively unveils a pivotal role of iNOS in scleroderma, highlighting its potential as a therapeutic target.